PROJECT SUMMARY/ABSTRACT Candidate: Dr. Attia's long-term goal is to improve lung health globally, conducting clinical research and trials in chronic lung diseases, with a focus on the role of HIV and other risk factors in influencing the pathophysiology and clinical course of lung disease. The research proposed in this application builds on her previous work, which found a significantly greater prevalence of chronic respiratory symptoms and abnormal spirometry among HIV+ adolescents compared to adults in a resource-limited setting. This K23 Career Development Award will provide Dr. Attia with essential research training to support her goal of becoming an independent investigator at the intersection of pulmonary disease, HIV and global health. Through this project, Dr. Attia will accomplish her immediate goals of attaining the expertise outlined in the following learning objectives: 1) training in measurement and analysis of lung growth in adolescents; 2) design and implementation of longitudinal studies; 3) quality control and monitoring of prospective studies; 4) advanced biostatistical methods to analyze complex data; and 5) responsible implementation of research activities in an international setting. These objectives will be achieved through a structured career development plan that incorporates formal coursework, mentoring by an advisory committee with collective expertise in pulmonary disease and lung growth, HIV, pediatrics, epidemiology, biostatistics and the use of biospecimens in clinical research, as well as protected time to gain practical research experience. Environment: The rich academic environment at the University of Washington (UW) is an ideal place for Dr. Attia's continued research training. UW is an outstanding biomedical research institution with a strong commitment to promoting the academic careers of promising investigators. The UW Division of Pulmonary and Critical Care Medicine is widely recognized for its Clinical Research Training Track and offers an intellectual environment that supports development of the skills necessary to collaborate with other investigators and achieve academic success. In addition to the resources and support provided within the Division, Dr. Attia will also have full access to the resources of the UW Department of Global Health Teaching, Research and Expert Education (TREE) program (directed by her co-mentor), which provides the administrative, clinical, laboratory and database management infrastructure that supports clinical research at the UW-affiliated Coptic Hope Center for Infectious Diseases in Nairobi, Kenya. Dr. Attia will receive directed training and mentoring in obtaining and analyzing spirometry in adolescents as a measure of lung growth and development through the resources of the UW Department of Pediatrics and the UW-led multi-site cystic fibrosis clinical trials network, Cystic Fibrosis Therapeutics Development Network. Dr. Attia will also have access to clinical research and biostatistical support through the UW School of Public Health and the Institute of Translational Health Sciences program (the Clinical and Translational Science Award program at UW). Research: Dr. Attia will examine differences in the prevalence, subtypes, risk factors and mechanisms of chronic lung disease, detected by baseline and repeat pre- and post-bronchodilator spirometry over 2 years in 150 HIV+ adolescents from the Hope Center compared to 150 HIV- controls, block-matched on age and sex. Among HIV+ adolescents, chronic lung disease will be further characterized with baseline chest CT scans. She will determine the role of HIV infection on the manifestations of chronic lung disease at baseline and the change in lung function over time, considering the complex interplay with other risk factors including malnutrition and indoor biofuel burning. She will also evaluate whether severity of HIV disease, and biomarkers of chronic immune activation and inflammation are associated with an increased prevalence of chronic lung disease and diminished lung function growth over time. The research proposed in this application is innovative because it signifies the first study to 1) directly characterize the epidemiology and pathophysiology of chronic lung disease in HIV+ compared to HIV- adolescents in a resource-limited setting, 2) ascertain risk factors associated with change in lung function over time, assessed by repeated spirometry, in HIV+ compared to HIV- adolescents, and 3) determine whether serum markers of chronic immune activation, inflammation and HIV severity are associated with chronic lung disease, providing potential mechanistic insights. Findings of this research will provide novel insights into the subtypes and pathophysiologic mechanisms of chronic lung disease development and progression in HIV+ adolescents in resource-limited settings, shedding light on risk factors and mechanisms that can be targeted by preventative and therapeutic interventions to mitigate the burden of chronic lung disease.